Michael Levin – Plasticity w/out genetic change: bioelectric embryos & synthetic proto-organisms Bioelectricity Podcast Notes

PRINT ENGLISH BIOELECTRICITY GUIDE

PRINT CHINESE BIOELECTRICITY GUIDE


Introduction: Beyond Genetics

  • Levin’s group studies how evolution uses a “multiscale competency architecture” and focuses on the “software” level (bioelectricity) rather than just the “hardware” (DNA).
  • Biology utilizes “agential materials”: Cells have inherent goals and problem-solving abilities, not just passive components.
  • Dynamic, robust anatomical homeostasis is a form of cellular collective intelligence, problem-solving in “morphospace.”
  • Developmental bioelectricity is a key “cognitive glue” coordinating cells to achieve large-scale anatomical outcomes.

The “Anatomical Compiler” – A Regenerative Medicine Goal

  • The long-term goal is an “anatomical compiler”: Software to translate a desired anatomical design into stimuli that guide cells to build it.
  • This would solve major medical problems like birth defects, injury, cancer, and aging by controlling cell group construction.
  • Current limitations: We lack models to predict anatomy from genomes alone, even in chimeric embryos (e.g., axolotl-frog hybrids).
  • Medicine focuses on “hardware” (genetics, pathways); understanding “software” (cellular decision-making) is crucial, especially in novel situations.

Cellular Intelligence and Robust Development

  • Embryogenesis isn’t hardwired: Cutting an embryo in half yields two normal individuals, showing adaptability.
  • Cells adjust to internal changes: Kidney tubule cells adapt to varying sizes, maintaining correct lumen diameter through different mechanisms.
  • Regeneration demonstrates anatomical homeostasis: A salamander limb regrows to the correct size and stops.
  • “Picasso tadpoles” with misplaced facial features develop into mostly normal frogs, demonstrating error correction.
  • Cells form networks, scaling up homeostatic loops. Single-cell goals (pH, hunger) expand to tissue/organ goals (limb length, finger count). Cancer involves cells reverting to primitive, single-cell goals.

Bioelectricity: The Cellular Communication Network

  • Cells use bioelectricity, like brains, but predating nervous systems: Ion channels create voltage potentials; electrical synapses (gap junctions) facilitate communication.
  • Early embryos use electrical networks to guide body plan development in “morphospace.”
  • Levin’s group manipulates bioelectricity *without* external fields or electrodes, but through ion channel modulation (optogenetics, drugs, mutations) and gap junction control.
  • Cancer cells disconnect electrically from neighbors. Forcing connection via ion channel expression can prevent tumor formation despite oncogene presence.
  • The “electric face” of frog embryos prefigures facial structure, showing a bioelectric memory of the correct form. Disrupting it causes mispatterning.
  • Ectopic organs (eyes, legs) can be induced by rewriting the bioelectric pattern in cells, acting as a modular “subroutine call.” Cells also recruit neighbors.

Brain Defect Repair and Planaria’s “Memories”

  • A bioelectric pre-pattern determines early brain shape. Computational models guide ion channel manipulation (e.g., hcn2) to restore the pattern and correct brain defects caused by teratogens.
  • Planaria (flatworms) regenerate any body part.
  • Bioelectric patterns store a stable “memory” of the number of heads. Altering this (without genetic changes) creates two-headed worms.
  • This altered body plan is stable through multiple cuttings, demonstrating a non-genetic, rewritable, long-term memory, analogous to incepting false memories.
  • Planaria’s bioelectric circuits have multiple stable states. Work is being undertaken on the State Space and the merging formalizations between Electrical Cirtuits, Formalisms and Connectionist Architechtures
  • Machine learning helps infer circuits and interventions for bioelectric control.
  • Planaria can be induced to grow heads of *other* species by manipulating electrical communication, demonstrating plasticity beyond their genome’s usual expression.

Xenobots: New Life Forms From Frog Cells

  • “Xenobots” are novel proto-organisms created from frog skin cells, with the *same* genome as tadpoles.
  • Removed from the normal embryonic context, these cells exhibit novel behaviors and a new developmental sequence *without* eons of selection.
  • This highlights the inherent potential of cells to explore “morphospace” and form new structures when constraints are removed, exploring new problems and how groups of cells could collectively adapt.

导言:超越基因

  • 莱文的研究小组研究进化如何利用“多尺度能力架构”,并专注于“软件”层面(生物电),而不仅仅是“硬件”层面(DNA)。
  • 生物学利用“自主材料”:细胞具有内在目标和解决问题的能力,而不仅仅是被动组件。
  • 动态、强大的解剖稳态是细胞集体智慧的一种形式,在“形态空间”中解决问题。
  • 发育生物电是一种关键的“认知粘合剂”,协调细胞以实现大规模的解剖结果。

“解剖编译器”——再生医学的目标

  • 长期目标是一个“解剖编译器”:将所需的解剖设计转化为刺激的软件,这些刺激引导细胞构建它。
  • 这将通过控制细胞群体的构建来解决主要的医学问题,如出生缺陷、损伤、癌症和衰老。
  • 当前的局限性:我们缺乏仅从基因组预测解剖结构的模型,即使在嵌合胚胎中(例如,蝾螈-青蛙杂交体)。
  • 医学专注于“硬件”(遗传学、通路);理解“软件”(细胞决策)至关重要,尤其是在新的情况下。

细胞智能和稳健发育

  • 胚胎发生并非硬连接:将胚胎切成两半会产生两个正常的个体,显示出适应性。
  • 细胞适应内部变化:肾小管细胞适应不同的大小,通过不同的机制保持正确的管腔直径。
  • 再生展示了解剖稳态:蝾螈的肢体再生到正确的尺寸并停止。
  • 面部特征错位的“毕加索蝌蚪”发育成大致正常的青蛙,表明了错误纠正。
  • 细胞形成网络,扩大稳态循环。单细胞目标(pH值、饥饿感)扩展到组织/器官目标(肢体长度、手指数量)。癌症涉及细胞恢复到原始的单细胞目标。

生物电:细胞通讯网络

  • 细胞使用生物电,就像大脑一样,但早于神经系统:离子通道产生电位;电突触(间隙连接)促进通讯。
  • 早期胚胎利用电网络在“形态空间”中指导身体计划的发育。
  • 莱文的小组在*没有*外部场或电极的情况下操纵生物电,而是通过离子通道调节(光遗传学、药物、突变)和间隙连接控制。
  • 癌细胞在电学上与邻近细胞断开连接。尽管存在致癌基因,但通过离子通道表达强制连接可以防止肿瘤形成。
  • 青蛙胚胎的“电面”预示了面部结构,显示了正确形式的生物电记忆。破坏它会导致图案错乱。
  • 可以通过重写细胞中的生物电模式来诱导异位器官(眼睛、腿),充当模块化的“子程序调用”。细胞也会招募邻近细胞。

脑缺陷修复和涡虫的“记忆”

  • 生物电预模式决定了早期大脑的形状。计算模型指导离子通道操纵(例如,hcn2)以恢复模式并纠正由致畸剂引起的大脑缺陷。
  • 涡虫(扁虫)再生任何身体部位。
  • 生物电模式存储了头部数量的稳定“记忆”。改变这一点(没有基因变化)会产生双头蠕虫。
  • 这种改变的身体计划在多次切割中是稳定的,证明了一种非基因的、可重写的、长期的记忆,类似于植入虚假记忆。
  • 涡虫的生物电回路有多个稳定状态。正在进行有关状态空间以及电路、形式化和联结主义架构之间合并形式化的工作。
  • 机器学习有助于推断生物电控制的电路和干预措施。
  • 通过操纵电通讯,可以诱导涡虫生长*其他*物种的头部,证明了超越其基因组通常表达的可塑性。

异种机器人:来自青蛙细胞的新生命形式

  • “异种机器人”是由青蛙皮肤细胞产生的新型原始生物,具有与蝌蚪*相同*的基因组。
  • 从正常的胚胎环境中移除后,这些细胞表现出新的行为和新的发育序列,*无需*长时间的选择。
  • 这突出了细胞在移除约束时探索“形态空间”并形成新结构的内在潜力,探索新的问题以及细胞群如何集体适应。